Most human cancers carry molecular rearrangements of the critical apparatus that control cell division. In many instances, two recently identified cell cycle inhibitors, p21/Waf1/Cip1 and p16/Ink4 fail to accumulate in response to negative growth signals, leading to the uncontrolled proliferation characteristic of cancer cells. During the Phase I stage of this grant, our experimental work will focus on the development of a novel yeast genetic system which will allow the rapid identification and characterization of short, hexameric peptide sequences that interact with Cdk4/Cyclin D1, and mimic the action of p16/Ink4. Cancer cells in which the activity of the Cdk4/Cyclin D1 kinase is upregulated due to cyclin D1 overexpression or lack of p16/Ink4, remain exquisitely sensitive to the inhibition of Cyclin D1 function, as tested by antibody/antisense microinjection. In Phase II the inhibitory peptides will be further characterized, and we will begin chemical modification to generate pharmacologically active derivatives. This research will lead to the development of new, highly specific antiproliferative agents. PROPOSED COMMERCIAL APPLICATION: Cancer represents one of the leading causes of death in the western world. The available drugs to treat cancer are highly toxic and their use leads to serious adverse side effects, that limit their efficacy. Mitotix is developing novel cancer therapeutics that block proliferation by targeting the rearrangements in cyclin- dependent kinase complexes present in cancer cells. The identified inhibitors could be used to treat more than fifty percent of all human tumors.